Impact of contraception and IVF hormones on metabolic, endocrine, and inflammatory status.

Thyroid dysfunction impairs menstrual cyclicity, female fertility, and pregnancy outcome, and is classified as the second most common endocrine disorder in women of reproductive age [ 6 ]. Impaired thyroid function predicts poor IVF fertilization outcome, emphasizing the importance of treating abnormal thyroid levels at the preconception stage [ 54 ]. Estrogen has a significant impact on thyroid-stimulating hormone (TSH) secretion and thyroid gland activity. During pregnancy, “estrogen dominance” interferes with thyroid metabolism by stimulating hepatic thyroxine-binding globulin secretion, thereby reducing levels of free thyroid hormones [ 55 ]. There is also a suppression of serum TSH level throughout pregnancy, with the lower normal level in the first trimester [ 56 , 57 ]. Furthermore, there is an increase in serum beta human chorionic gonadotrophin hormone during pregnancy (β-HCG; pregnancy indicator hormone), the effect being particularly pronounced in twin pregnancies. β-HCG has stimulatory effects at the TSH receptor and may drive over-production of thyroid hormones during pregnancy, and also contribute to suppression of TSH production [ 58 ]. Recurrent pregnancy loss, preterm birth, and placenta abruption have been associated with high TSH level [ 6 , 54 ]. Oral contraceptives and pregnancy alter thyroid function in similar ways, probably through estrogenic effects. However, although the mechanisms are similar, pronounced changes in thyroid hormones occur in pregnancy compared with the use of oral contraceptive therapies. The difference in magnitude of thyroid effects between pregnancy and oral contraceptive therapies likely relates to exogenous estrogen therapy having a dose-dependent effect on increasing serum thyroxine-binding globulin and total serum thyroxin levels in those with normal thyroid function [ 43 , 59 ]. Regarding IVF therapies, in addition to exogenous estrogen, gonadotrophin-releasing hormone (GnRH) is also administered, the latter having been reported to affect levels of thyroid hormones (likely through indirect stimulation of gonadotrophin release and increased production of estrogen) [ 60 ]. There is a lack of data in the current literature on thyroid status in IVF-conceived versus spontaneously conceived pregnancies. Given the potential for cumulative effects of estrogen-related thyroid dysfunction during IVF-conceived pregnancies, this should be a focus for future research.

Despite a steady increase in the medical treatment of infertility with ART, there is still a lack of published evidence on their safety. Compared with other ART treatments, IVF treatment predisposes to increased maternal risks and complications, since there is alteration of the normal physiological development of pregnancy during IVF. Furthermore, use of stimulating agents can also adversely affect pregnancy outcome, including association with ovarian cysts, ovarian enlargement, and ovarian hyper stimulation syndrome (OHSS) [ 3 ]. Ectopic pregnancy is twice as common, and pregnancy loss after 12 weeks is more prevalent with IVF-conceived pregnancies [ 8 ]. Furthermore, multiple pregnancies account for 25% of IVF-conceived pregnancies [ 9 ]. However, although twin and triplet pregnancies have a higher complication rate overall compared with singleton ones (including preeclampsia, gestational diabetes mellitus (GDM), thromboembolism, and preterm delivery), complication rates overall are similar between IVF-conceived and spontaneously conceived pregnancies [ 10 , 11 ]. Future studies should focus on obstetric outcomes with IVF-conceived pregnancies in larger cohorts, well matched with spontaneous pregnancies, including those that result in multiple pregnancies. One reason for higher rates of maternal adverse outcomes with IVF may relate to the frequent categorization of women undergoing IVF as “high risk,” as they usually present with advanced age, high BMI (> 30 kg/m 2 ), or a pre-existing medical condition such as PCOS [ 12 ]. A higher prevalence of spontaneous abortion occurs in IVF-conceived pregnancies in women who are also obese and/or have a history of PCOS [ 13 ]. IVF-conceived pregnancy is a “high-risk” intervention with increased risk for maternal and obstetric complications. These include miscarriage, vaginal bleeding, frequent hospitalization, GDM, gestational hypertension, and preterm labor [ 14 , 15 ]. However, there is some controversy in the literature regarding the actual risk of adverse obstetric and maternal outcomes with IVF: in a large retrospective study by Kozinszky et al. [ 10 ], data did not show increased rates of obstetric complications with IVF-conceived pregnancy. Cesarean section is more common with IVF. Women may consider IVF-conceived pregnancy as “precious” after many years of infertility and choose cesarean section to prevent perceived complications from a natural delivery, and not necessarily because of medical necessity [ 16 ]. Compared with spontaneously conceived pregnancy, women with IVF-pregnancies are more likely to develop GDM. This association remains following adjustment for maternal and gestational age, and parity [ 17 ]. It is possible that the increased risk for GDM in IVF-conceived pregnancies may stem from association with prenatal obesity or maternal PCOS (conditions that are not always specified) [ 18 ]. Furthermore, association of IVF with GDM may develop indirectly from the effects of IVF therapy on body fat accumulation, or directly from the procedure itself, through incompletely understood mechanisms. IVF may also associate with increased risk of breast and ovarian cancer post-IVF, although this association remains poorly described and more studies are needed [ 19 ]. Risk of congenital malformation was shown to associate with IVF, especially with multiple pregnancies. Mixed reports exist regarding fetal outcomes of IVF. While some studies suggest that IVF may predispose to intrauterine growth retardation, fetal anomalies, birth defect, and perinatal mortality [ 20 , 21 ], others show no difference in fetal outcomes between spontaneous and IVF-conceived pregnancies [ 22 , 23 ]. In one study, it was shown that IVF-conceived children are predisposed to obesity, insulin resistance, type 2 diabetes mellitus (T2D), and cardiovascular disease in adulthood [ 24 ]. Further prospective studies are required to clarify adverse effects of IVF on offspring, regarding both fetal development and longer term effects that manifest in adulthood.

The increased risk of complications and adverse outcomes of IVF-conceived pregnancies remain contentious. However, maternal preconception characteristics are likely to play a role. This promotes the importance of screening high-risk populations at preconception, and early management of controllable factors to prevent possible obstetric complications and predict IVF success. The impact of pregnancy on metabolic, endocrine, and inflammatory parameters is well established. However, similar data in IVF-conceived pregnancies are lacking. Identifying early maternal metabolic and inflammatory biomarkers during IVF therapy and IVF-conceived early pregnancy may act as predictors for future maternal and fetal problems during the ensuing pregnancy. Such predictive factors could improve both pregnancy and fetal outcomes of IVF therapies.

Infertility is a global health concern and affects 20% of couples of reproductive age. The use of assisted reproductive technologies (ART), including primarily in vitro fertilization (IVF), is becoming more prevalent. Oral contraceptive hormones commonly associate with gastrointestinal side effects from changes in gut microflora, in addition to possible adverse effects on glucose and lipid metabolism, which in turn may promote insulin resistance and inflammation. The concentration of reproductive hormones is much higher when used for IVF than oral contraception. However, confirmation of the safety of IVF (both maternal and fetal) remains tenuous. Previous studies have focused mainly on risk of obstetric complications and fetal outcomes in IVF-conceived pregnancies, with relatively few studies investigating the possible effects of IVF hormones on maternal metabolic, endocrine and inflammatory status, and the relationship to the known diabetogenic and atherogenic effects of pregnancy. Regarding the inflammatory response, the intestinal microbiota is of particular interest, given its central role in the modulation of immune-regulation (including during pregnancy), and insulin sensitivity. It would be desirable to have reliable predictive factors for possible metabolic, endocrine, and inflammatory sequelae of IVF therapies. Such factors could help prevent, or at least identify, at an early stage potential maternal and/or fetal complications, such as onset of gestational diabetes. In this brief review, we outline existing literature regarding the potential adverse maternal and fetal outcomes of exogenously administered reproductive hormones (oral contraception and IVF) on glucose and insulin homeostasis, metabolic profile, and inflammatory status. Infertility is defined as the “inability to conceive after 12 months of unprotected intercourse, and 6 months for women 35 years of age and older” [ 1 ]. Globally, 15–20% of couples are infertile, and this corresponds to 35% female infertility, 30% male infertility, and 20% combination of the two, and the remaining 15% of cases corresponds to idiopathic or unexplained infertility [ 2 , 3 ]. Many factors are associated with infertility in women. Mechanical impairment of the reproductive system accounts for about 35% of female infertility and includes damaged or blocked fallopian tubes, fibroids, and endometriosis. Age has a significant impact on female fertility, affecting both quality and quantity of eggs: reproductive age peaks in the 20s and early 30s and starts to decline after the age of 35 years [ 1 ]. Ovulation and hormonal-related disturbances are common causes of female infertility. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is associated with obesity, hyperinsulinemia, and insulin resistance [ 4 ]. Although frequently co-existent with PCOS, there is evidence to support the notion that overweight and obesity are independent contributors to female infertility, mediated through adverse effects on reproductive hormones, manifesting as anovulation [ 5 ]. Thyroid dysfunction is also a common endocrine disorder to impair menstrual cyclicity and female fertility [ 6 ]. In men, fertility is adversely affected by advanced age, smoking, and obesity, similar to women, although age-related effects are less pronounced, with fertility only declining in men after the age of 50 years [ 7 ].